Synthetic Cannabinoids Raise Blood Pressure Through a Mechanism Unrelated to Cannabinoid Receptors | Research

The takeaway

In rats, synthetic cannabinoids found in "Spice" products lowered body temperature through CB1 receptors but raised blood pressure through an independent mechanism involving the sympathetic nervous system.

Readers concerned about the cardiovascular dangers of synthetic cannabinoids.

Blood pressure elevation from synthetic cannabinoids was NOT blocked by cannabinoid receptor antagonists

What the researchers found

Researchers compared THC and four synthetic cannabinoids (CP55,940, JWH-018, AM2201, XLR-11) found in "Spice" products. All compounds produced dose-dependent hypothermia (temperature drops) that was blocked by the CB1 antagonist rimonabant, confirming cannabinoid receptor involvement.

However, the synthetic cannabinoids also elevated blood pressure during the first hour, and this hypertensive effect was NOT blocked by either rimonabant or the neutral CB1 antagonist AM4113. Instead, the blood pressure increase was blocked by the ganglionic blocker hexamethonium and the alpha-1 adrenergic antagonist prazosin.

This revealed a dual mechanism: hypothermia was cannabinoid receptor-mediated, but the blood pressure elevation was driven by increased central sympathetic nervous system outflow, independent of cannabinoid receptors. This non-cannabinoid cardiovascular effect may explain why synthetic cannabinoid users experience cardiovascular emergencies that would not be expected from CB1 receptor activation alone.

Why it matters

Synthetic cannabinoid-related cardiovascular emergencies (heart attacks, strokes, hypertensive crises) are a growing clinical problem. This study reveals that these cardiovascular effects occur through a mechanism separate from the cannabinoid receptors, explaining why they may be more dangerous than natural cannabis and why CB1 antagonists alone may not reverse them.

The numbers in context

Potency ranking for hypothermia: CP55,940 > AM2201 = JWH-018 > THC = XLR-11. Blood pressure elevation occurred in the first hour. Rimonabant blocked hypothermia but NOT blood pressure effects. Hexamethonium and prazosin blocked the blood pressure increase.

How the study worked

Male rats received subcutaneous injections of THC or synthetic cannabinoids. Biotelemetry transmitters measured body temperature and blood pressure continuously for 3 hours. Antagonists were used to identify receptor mechanisms. Potency rankings were established across compounds.

What this study cannot tell us

Animal study using subcutaneous injection, which differs from the typical human route of smoking/vaporizing. Only four synthetic cannabinoids were tested, while hundreds exist in the recreational market. Blood pressure and temperature are surrogate measures; direct cardiac effects were not assessed. Chronic exposure effects were not studied.

How to read the evidence

Preliminary evidence from a single animal study, though with strong mechanistic dissection using multiple antagonists.

When this study was published

Published in 2017. Synthetic cannabinoid cardiovascular emergencies remain an ongoing public health concern.

The bigger picture

This study has direct clinical implications: emergency treatment of synthetic cannabinoid overdose with cardiovascular complications may require alpha-adrenergic blockers or sympatholytic agents, not cannabinoid receptor antagonists. The separation of "cannabinoid" (temperature) and "non-cannabinoid" (blood pressure) effects explains why synthetic cannabinoids are clinically more dangerous than natural cannabis.

Questions still open

Do all synthetic cannabinoids raise blood pressure through the same non-CB1 mechanism? Would alpha-adrenergic blockers be effective clinical treatments for synthetic cannabinoid-related hypertensive crises? What structural features of synthetic cannabinoids determine their off-target cardiovascular effects?

Common questions

Why are synthetic cannabinoids more dangerous for the heart than natural cannabis?

This study shows that synthetic cannabinoids raise blood pressure through a mechanism completely separate from cannabinoid receptors, likely involving the sympathetic nervous system. Natural THC acts primarily through cannabinoid receptors. The "off-target" cardiovascular effects of synthetic cannabinoids create dangers that natural cannabis does not.

Can synthetic cannabinoid overdoses cause heart attacks?

Synthetic cannabinoid use has been associated with heart attacks, strokes, and other cardiovascular emergencies in clinical reports. This study provides a mechanistic explanation: they increase blood pressure through sympathetic activation independent of cannabinoid receptors, creating cardiovascular stress that pure cannabinoid receptor activation would not.

Read the original research

Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.

Drug and alcohol dependence, 179, 387-394

View on PubMed ↗Publisher’s paper ↗

Citation

Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H. (2017). Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.. Drug and alcohol dependence, 179, 387-394. https://doi.org/10.1016/j.drugalcdep.2017.07.029